Until our recent pharmacologic studies, digitalis has been assumed to elevate vascular resistance in the peripheral circulation and in the heart through a direct effect on vascular smooth muscle. Over the last 6 years, we have demonstrated that the increase in resistance associated with intravenous digitalis in both heart and skeletal muscle occurs through neurogenic stimulation of peripheral alpha adrenergic receptors. The site of action of digitalis appears to be in the central nervous system. The purpose of the proposed pharmacologic studies is to characterize the neurogenic effects of digitalis on cardiovascular control. The proposed studies will define more precisely the peripheral neurogenic vasoconstrictor effects of digitalis on the arterial circulation. They will determine how these neurogenic vasoconstrictor effects relate to other vasoactive influences - which may originate either locally or remotely. For example, it is proposed to examine the neurogenic vasoconstrictor effects in the heart under conditions of severe regional ischemia. It is planned to continue our observations on the effects of elevated background sympathetic activity, produced by systemic hypotension, on the neurogenic effects of digitalis on coronary and skeletal muscle vascular resistance. It is also planned to extend the concept that digitalis exerts a neurogenic effect on the peripheral vasculature to the venous circulation. In this regard, preliminary data suggest that adrenergic effects of digitalis are not limited to the arterial circulation but affect venous capacity as well. Therefore, studies will be undertaken to examine the contribution of adrenergically mediated effects of digitalis on the venous circulation and to compare these effects with those produced by a direct effect of digitalis. Thus, the proposed studies will provide not only basic pharmacologic information on the mechanisms of action of this frequently used group of drugs, but they should also provide knowledge about the neurogenic effects of digitalis, which will be directly applicable to clinical medicine and various disease states.